GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION IN BABOONS: IMMUNOLOGICAL AND FUNCTIONAL STUDIES (PI/PD: David K.C. Cooper) OVERVIEW OF THE PROGRAM PROJECT SUMMARY/ABSTRACT Our program has produced genetically-engineered pigs that protect the pig organ from injury by the primate innate immune response. Organs transplanted from these pigs, together with an effective (and potentially clinically-applicable) immunosuppressive regimen, have markedly extended pig graft survival in baboons to months or even years. The current proposal aims to confirm that the combination of a multi-gene pig and an effective immunosuppressive regimen will allow consistent function of life- supporting pig kidneys (Project 1) and hearts (Project 3) for 6 months or longer, and of life-supporting livers for 1 month (to act as a bridge to liver allotransplantation [Project 2]). The work in the 3 Projects will be supported by 4 Cores. Core A (Pig Core) will provide specific multi-gene pigs (to Projects 1-3) that have 8 or more genetic manipulations that will help overcome the remaining barriers to moving towards clinical trials. Core B (Immunobiology Core) and Core C (Histopathology Core) will provide evidence of the mechanisms for the problems being investigated and the therapeutic approaches being explored. Core D (Administrative Core) will provide an organizational structure to facilitate the success of the proposed Projects. Our Aims include (i) exploring methods of preventing or suppressing the adaptive immune response through either novel pig genetics or pharmacologic interventions, (ii) preventing or reducing the thrombocytopenia that immediately follows pig liver transplantation in baboons, (iii) preventing or reducing the rapid growth of pig organs documented early after transplantation into baboons, and (iv) comprehensively monitoring function of the kidney, liver, and heart after transplantation into baboons in the presence of a controlled immune response (i.e., in the relative absence of an immune response). The mechanisms whereby the combination of genetic modification and refinements to the immunosuppressive regimen prolong graft survival will be investigated by immunological assays and histopathology techniques. Success in Projects 1 and 3 would allow immediate consideration of limited clinical trials of kidney and/or heart xenotransplantation. Success in Project 2 would allow immediate consideration of a limited clinical trial in which a pig liver is transplanted as a life-sustaining bridge to allotransplantation. The overall goal of the 3 projects, therefore, is to advance the science during this 5-year period of funding so that clinical trials of kidneys and hearts can be initiated as destination therapies (or, in the case of the heart, possibly initially as a bridging therapy), and of pig livers as bridging to allotransplantation.